Selectins are a family of molecules, including ELAM-1 (endothelial leukocyte adhesion molecule-1), GMP-140 (CD62; PADGEM) and LECCAM-1 (Mel-14 in mice, Leu-8 in humans), which primarily mediate adhesion of blood cells and tumor cells expressing specific carbohydrate epitopes to endothelial cells (EC's) and to platelets. The molecules share a structural motif consisting of an N-terminal lectin domain (carbohydrate-binding domain), an epidermal growth factor (EGF) domain, a complement-regulatory sequence repeat, a transmembrane domain and a cytoplasmic C-terminal domain.
The lectin domains of ELAM-1 and GMP-140 bind to the carbohydrate structures sialosyl-Le.sup.x (SLe.sup.x) (Lowe et al., Cell, 63: 475, 1990; Phillips et al., Science, 250: 1130, 1990; Polley et al., Proc. Natl. Acad. Sci., U.S.A., 88: 6224, 1991) and sialosyl-Le.sup.a (SLe.sup.a) (Berg et al., J. Biol. Chem., 266: 14869, 1991; Takada et al., Biochem. Biophys. Res. Commun., 179: 713, 1991; Handa et al., Biochem, Biophys. Res. Commun., in press). Because SLe.sup.x and SLe.sup.a are tumor-associated antigens (Hakomori, Adv. Cancer Res., 52: 331, 1989), selectins likely play important roles in defining tumor cell adhesion to platelets and EC's and in initiating metastasis (Hakomori, Curr. Opin. Immunol., 3: 646, 1991).
Interaction of leukocytes recruited to an inflammatory locus with activated vasculature endothelial cells, or with activated platelets, is an initial event in inflammation. In general, however, the number of recruited leukocytes is excessive resulting in, for example, infiltration of leukocytes through the vessel walls into surrounding tissue or development of emboli and microemboli resulting from the aggregation of leukocytes with platelets or other blood cell components.
Interaction between tumor cells and activated platelets or activated vasculature endothelial cells can result in events similar to those described above for leukooytes, namely adhesion and development of emboli and mioroemboli. Adhesion of tumor cells to endothelial cells and extravasation or extravascularization of tumor cells are regarded as early events of metastasis.
In the adhesion of either leukocytes or tumor cells to endothelial cells or platelets, interleukin-1 (IL-1) is produced by leukocytes IL-1 induces the expression of ELAM-1. Many tumor cells produce TGF.beta. or TNF.alpha. which activate endothelial cells and induce expression of ELAM-1. Further, both leukocytes and tumor cells release enzymatic factors and ADP which activate platelets and induce expression of GMP-140.
ELAM-1 and GMP-140 are instrumental in mediating adhesion of tumor cells or leukocytes that express SLe.sup.a or SLe.sup.x to endothelial cells. Similarly, activated platelets expressing GMP-140 adhere tumor cells or leukocytes expressing SLe.sup.a or SLe.sup.x.
Accordingly, it would be beneficial to minimize or to prevent adhesion of leukocytes or tumor cells to endothelial cells or to platelets through inhibition of selectin expression, or of SLe.sup.a or SLe.sup.x expression on leukocytes or tumor cells, thereby minimizing or preventing thromboses/embolism, inflammation, tissue damage and metastasis resulting therefrom.